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Mediation of Anorexia by Human Recombinant Tumor Necrosis Factor through a Peripheral Action in the Rat¹

The Cotzias Laboratory of Neurooncology [R. J. B., G. W. P., D. P.], The Surgical Metabolism Laboratory [R. W.], The Laboratory of Peptide Hormone Action [D. B. D.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021; Department of Psychology and Neuropsychology Doctoral Sub-Program, Queens College, City University of New York, Flushing, New York 11367 [R. J. B., P. E. M.]; Departments of Neurology and Pharmacology, Cornell University Medical College, New York, New York 10021 [G. W. P.]

Human recombinant tumor necrosis factor (TNF) produces significant anorexia in the rat which persists for up to 24 h after a single dose (5 µg/325 g rat). Dose-response studies indicate similar potencies for TNF following central or peripheral administration. Brain ¹²⁵I-TNF levels were more than 100-fold greater after intracerebroventricular than i.v. injection, whereas blood levels of radioactivity were quite similar following both routes of administration. Gel filtration chromatography and precipitation by trichloroacetic acid showed that the radioactive label which exited the central nervous system was associated with intact TNF. The rapid effusion of ¹²⁵I-TNF from the central nervous system resulted in detection of similar levels of the cytokine in a number of important target tissues (skin, muscle, fat) relative to that detected after peripheral administration. After i.v. or intracerebroventricular administration, blood levels of TNF declined rapidly to nearly undetectable levels over 4 h. However, the anorexia induced by TNF was sustained, and feeding remained depressed between 6 and 24 h postadministration. These observations suggest that TNF produces its anorectic effects at peripheral sites, possibly through mediators.

¹ This work was supported by Grants PDT 169 from the American Cancer Society (G. W. P.), DK 30788 from NIH (D. B. D.), CA 44747 from the National Cancer Institute (D. B. D.), and by a sabbatical leave (R. J. B.) from Queens College to Memorial Sloan-Kettering Cancer Center. R. W. was supported by Grants CA 09501 and CA 38858 from the National Cancer Institute. D. B. D. is especially grateful for a special grant for research from the New York City Division of the American Cancer Society (BC 620). The support of a core grant from the National Cancer Institute (CA 08748) to Memorial Sloan-Kettering Cancer Center is acknowledged.

² Present address: Department of Surgery, University of California, San Francisco, CA 94143

³ To whom requests for reprints should be addressed, at The Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.

Received 2/ 2/89. Revised 6/ 8/89. Revised 8/17/89. Accepted 8/22/89.

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